Totsuka K, Shimizu K, Konishi M, Yamamoto S
Tokyo Women's Medical College, Japan.
Antimicrob Agents Chemother. 1992 Apr;36(4):757-61. doi: 10.1128/AAC.36.4.757.
The metabolism and pharmacokinetics of pivalic acid, a major metabolite of S-1108, were studied with three healthy volunteers. Concentrations of S-1006 (the active compound), pivalic acid, and pivaloylcarnitine in plasma and urine were measured after administration of S-1108. Recoveries in urine at the doses of S-1108 given (100 and 200 mg) were 33 to 41% for S-1006, 93% for total pivalic acid, and 89 to 94% for pivaloylcarnitine in 24 h, and maximum concentrations in plasma were 2 micrograms of S-1006 per ml, 1 micrograms of total pivalic acid per ml, and 2 micrograms of pivaloylcarnitine per ml after a 200-mg oral administration of S-1108. More than 90% of the pivalic acid was excreted as pivaloylcarnitine, and no measurable amount of free pivalic acid was present in urine samples, indicating that the pivalic acid liberated from S-1108 was almost quantitatively conjugated with carnitine in the human body. The level of free carnitine in plasma was unaffected by a single 200-mg administration of S-1108, whereas urinary excretion of free carnitine decreased as levels of acylcarnitine increased. The acylcarnitines were excreted primarily in the form of pivaloylcarnitine. This study clearly showed how the pivalic acid was metabolized and excreted in humans. The importance of monitoring carnitine, an essential cofactor in fatty acid metabolism, was also discussed in terms of its utilization by pivalic acid.
用三名健康志愿者对S - 1108的主要代谢产物新戊酸的代谢和药代动力学进行了研究。给予S - 1108后，测定血浆和尿液中S - 1006（活性化合物）、新戊酸和新戊酰肉碱的浓度。给予S - 1108（100和200mg）剂量后，24小时内尿液中S - 1006的回收率为33%至41%，总新戊酸为93%，新戊酰肉碱为89%至94%；口服200mg S - 1108后，血浆中最大浓度分别为每毫升2微克S - 1006、每毫升1微克总新戊酸和每毫升2微克新戊酰肉碱。超过90%的新戊酸以新戊酰肉碱的形式排泄，尿液样本中未检测到可测量的游离新戊酸，这表明S - 1108释放的新戊酸在人体内几乎定量地与肉碱结合。单次给予200mg S - 1108对血浆中游离肉碱水平无影响，而游离肉碱的尿排泄量随酰基肉碱水平的升高而降低。酰基肉碱主要以新戊酰肉碱的形式排泄。这项研究清楚地表明了新戊酸在人体内是如何代谢和排泄的。还从新戊酸对其利用的角度讨论了监测肉碱（脂肪酸代谢中的一种必需辅助因子）的重要性。
